ABSTRACT Alzheimer?s disease and related dementias (ADRD) are progressive and irreversible neurodegenerative disorders that affect 10% of Americans over the age of 65. Genetic and environmental factors, including excessive alcohol consumption, modify ADRD risk. In the US, 10.2% of pregnant women report alcohol consumption and 3.2% report binge drinking. The consequence of this prenatal alcohol exposure (PAE) is Fetal Alcohol Spectrum Disorder (FASD), that encompasses a range of outcomes featuring neurodegeneration and persistent behavioral deficits affecting cognition, learning and memory, and sensory processing. Those with FASD have striking impairments in cognitive flexibility, and the current award investigates the cholinergic systems responsible for these cognitive deficits. ADRD and FASD affect the same cognitive domains, brain subregions, and feature cholinergic impairments; mechanistically, both pathologies are driven, in part, by neuroinflammation. Our recent transcriptome analyses in two independent models of PAE identified significant neuronal upregulation of AD-related genes (PSEN1, PSEN2, APP, BACE1, and APOE) and this persisted into adolescence. These findings suggest that PAE, as with adult alcohol abuse, may increase ADRD risk in later life. Surprisingly, no one has ever tested whether PAE increases ADRD risk; a single self-study suggests those with FASD have premature dementia. In this supplement request, we will test the novel hypothesis that PAE is a prenatal ?primer? that accelerates the progression and/or severity of AD-related pathologies and behavioral impairments. We test this hypothesis using two novel resources. In the first, we test whether PAE accelerates ADRD progression using an established AD model, the 3xTg-AD mice, which were engineered to express human PSEN1, MAPT, and APP and display early-onset AD. In the second, we test whether PAE increases risk for AD in our unique cohort of aged, wild-type C57BL/6J mice (born March-June 2018). Subaim 4A evaluates whether PAE increases the deposition of amyloidosis and tau tangles (cortex, hippocampus) in aged B6J and 3xTg-AD mice. Subaim 4B tests if PAE causes a decline in behavioral performance in aged B6J that worsens with age, and whether PAE and ADRD interact in 3xTg-AD mice to accelerate that behavioral decline. 3xTg-AD are tested at ages with intermediate pathology (3mo-9mo) to avoid a potential ceiling effect of PAE- AD interaction. Aged wild-type mice are tested at ages 3mo & 10mo (done), and 17mo and 24mo (this supplement). This hypothesis represents a novel risk factor for ADRD, and reflects their mechanistic, behavioral, and pathological similarities. This pilot study provides core preliminary data in support of a larger, mechanistic-driven R01 that will continue to investigate the role of alcohol in the etiology of AD. Using biomarkers and models from the AD field allows integration with that body of work. Understanding the long- term pathologies that can result from PAE will be critical to supporting people with FASDs and to guide research into interventions that improve their quality of life and behavioral performance.